Project Summary Sleep disordered breathing (SDB) is a highly prevalent disease that has become an increasingly recognized, potent cause of cardiovascular disease. Cumulatively, SBD is associated with ~3 fold increased odds of fatal and non-fatal cardiovascular events, which can be reversed with effective treatment. The prevalence and severity of SDB are greatly amplified at high altitudes (>2500m above sea level), in which an estimated 150 million people live worldwide. In our research center located in Puno, Peru (3825m above sea level), we have documented an ~80% prevalence of SDB in a population-based community sample, indicating that highlanders are exposed to significant reductions in oxyhemoglobin saturation and recurrent apneic episodes during sleep. Nevertheless, SDB remains largely unrecognized and untreated in Peruvian highlanders, adding significantly to their overall burden of cardiovascular disease. The current proposal addresses this critical unmet need for an easily deployed SDB therapy in highland populations of low to middle income countries (LMIC). It is based on recent data from our highland cohort, which demonstrates that: (1) sleep greatly amplifies daytime hypoxemia and exposes subjects to recurrent apneic episodes, (2) oxygenation improves markedly when highlanders sleep on an incline rather than in the horizontal plane, and (3) SDB in highlanders is closely linked to markers of cardiometabolic stress. These findings lead us to hypothesize that a simple, readily deployed nocturnal postural maneuver will effectively treat SDB and reduce cardiometabolic stress in highlanders. To address this hypothesis, we will conduct a 12 week Phase II single-center, randomized controlled clinical trial in 60 highlanders to examine SDB treatment responses and adherence, and related cardiometabolic outcomes in Puno, Peru. Our primary hypothesis is that subjects who sleep on an incline compared to sleeping flat will demonstrate significant improvements in SDB including mean nocturnal oxyhemoglobin desaturation and apnea-hypopnea index. Our secondary hypotheses are that (1) participants will adhere to the intervention, and that (2) postural therapy will decrease metabolic dysfunction (fasting glucose, glucose tolerance, lipids), cardiovascular stress (blood pressure, vascular reactivity), and markers of hypoxemia (hemoglobin, erythropoietin, vascular endothelial growth factor receptor 1). If successful, this study will demonstrate that postural therapy is well tolerated and reverses underlying nocturnal defects in ventilation and oxygenation in highlanders. It will inform the design of a pivotal phase III trial with estimates of sample sizes for clinically relevant cardiometabolic outcomes. It will also set the stage for head to head comparisons of postural therapy with conventional devices (e.g., non-invasive positive pressure ventilation), which are costly, cumbersome, poorly tolerated, and often ineffective in treating SDB at altitude. We can also envision scenarios in which similar benefits of postural therapy can be applied broadly to patients with underlying cardiopulmonary diseases who usually have SDB, regardless of altitude.